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. 2015 Jul 9;7(1):63.
doi: 10.1186/s13148-015-0106-0. eCollection 2015.

Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX

Dae-Won Lee  1 , Sae-Won Han  2 , Yongjun Cha  1 , Ye Young Rhee  3 , Jeong Mo Bae  3 , Nam-Yun Cho  3 , Kyung-Hun Lee  1 , Tae-Yong Kim  1 , Do-Youn Oh  2 , Seock-Ah Im  2 , Yung-Jue Bang  2 , Seung-Yong Jeong  4 , Kyu Joo Park  4 , Gyeong Hoon Kang  3 , Tae-You Kim  5
Affiliations

Different prognostic effect of CpG island methylation according to sex in colorectal cancer patients treated with adjuvant FOLFOX

Dae-Won Lee et al. Clin Epigenetics. .

Abstract

Background: Profound methylation of CpG islands constitutes a distinct molecular subtype of colorectal cancer (CRC). The frequencies of methylation in CRC vary according to clinico-pathological characteristics including sex. However, interaction between these characteristics and prognostic influence of methylation status has not been clearly defined. We have investigated the prognostic role of promoter methylation using eight CpG island methylator phenotype (CIMP) markers in 497 stage II or III CRC patients who underwent curative resection followed by adjuvant FOLFOX. Overall survival (OS) and disease-free survival (DFS) were compared between subgroups classified by methylation status, and interactions with clinico-pathological features were analyzed.

Results: CIMP-high (≥5 methylated loci) and concurrent methylation in NEUROG1 and CDKN2A (p16) were found in 5.8 and 7.9 % of patients, respectively. Although CIMP-high status was not associated with survival, concurrent methylation in NEUROG1 and CDKN2A (p16) was associated with shorter OS and DFS. Moreover, the prognostic role of the concurrent methylation was different among sex. The negative prognostic impact was only observed in male but not in female (interaction p value = 0.026 for OS and 0.011 for DFS). In male, the 5-year OS was 61.6 % in concurrent methylation (+) and 91.7 % in concurrent methylation (-) (p < 0.001) whereas it was 95.0 and 92.8 % in female, respectively (p = 0.78).

Conclusions: Concurrent methylation in NEUROG1 and CDKN2A is associated with poor survival in CRC treated with adjuvant FOLFOX. Interaction analysis indicates that the prognostic role is different according to sex.

Keywords: Colorectal cancer; CpG islands methylator phenotype; FOLFOX; Sex.

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Figures

Fig. 1
Fig. 1
Kaplan-Meier curves of overall survival and disease-free survival according to CIMP status (a, b) and concurrent methylation of NEUROG1/CDKN2A (p16) (c, d). Co-methylation concurrent methylation, N number
Fig. 2
Fig. 2
Forest plot demonstrating the risk of death by concurrent methylation (+) compared to concurrent methylation (−) stratified by clinico-pathological factors. All hazard ratios were adjusted by histology, angiolymphatic invasion, and perineural invasion. N number, HR hazard ratio, CI confidence interval, WT wild type, MT mutation type
Fig. 3
Fig. 3
Kaplan-Meier curves of overall survival (OS) and disease-free survival (DFS) according to concurrent methylation of NEUROG1/CDKN2A (p16) stratified by sex. (a) Male: OS. (b) Female: OS. (c) Male: DFS. (d) Female: DFS. Co-methylation concurrent methylation, N number
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